Bleomycin is an important anti-cancer drug whose usefulness is limited by the occurrence of pulmonary fibrosis. The overall objective of this proposal is to further our understanding of bleomycin-induced pulmonary fibrosis through the identification of early cellular and biochemical markers, through the rational pharmacologic intervention of the abnormal lung connective tissue accumulation that hallmarks the limiting toxicity of this useful cancer chemotherapeutic drug and through in vitro analysis of macrophage-fibroblast interactions. Specifically, we will use a rat model of bleomycin-induced pulmonary fibrosis that is produced by a single intratracheal instillation of drug. As an enzymatic marker for early connective tissue changes, we will determine the correlation of prolyl hydroxylase activity with histologic alterations. In addition, as a specific marker of drug-induced lung endothelial cell damage, we will determine the activity of angiotensin-l-converting enzyme and the relationship of this biochemical parameter to stages in the development of bleomycin-induced lung injury. We will then assess the impact of the collagen sythesis inhibitor L-dehydroproline on pulmonary collagen metabolism, histopathology and anti-cancer activity of bleomycin. We will define the levels of both prolyl hydroxylase and angiotensin converting enzyme activities in pulmonary lavage fluid from normal and fibrotic lungs as sensitive and accessible indicators of connective tissue activation in the fibrotic lung disorders. We will examine biologic products of bleomycin activated macrophages for their effect on collagen synthesis, fibroblast mitosis and the presence of prostaglandins, cyclic AMP and collagenase. Finally, we will test bleomycin analogues in our rat model system for their potential to cause pulmonary alterations in order to establish the applicability of our system as a screen for pulmonary toxicity.